Distinct associations of NEDD4L expression with genetic abnormalities and prognosis in acute myeloid leukemia

Abstract

Background There is mounting evidence that demonstrated the association of aberrant NEDD4L expression with diverse human cancers. However, the expression pattern and clinical implication of NEDD4L in acute myeloid leukemia (AML) remains poorly defined. Methods We systemically determined NEDD4L expression with its clinical significance in AML by both public data and our research cohort. Moreover, biological functions of NEDD4L in leukemogenesis were further tested by in vitro experiments. Results By the public data, we identified that low NEDD4L expression was correlated with AML among diverse human cancers. Expression of NEDD4L was remarkably decreased in AML compared with controls, and was confirmed by our research cohort. Clinically, low expression of NEDD4L was correlated with greatly lower age, higher white blood cells, and higher bone marrow/peripheral blood blasts. Moreover, NEDD4L underexpression was positively correlated with normal karyotype, FLT3 and NPM1 mutations, but negatively associated with complex karyotype and TP53 mutations. Importantly, the association between NEDD4L expression and survival was also discovered in cytogenetically normal AML patients. Finally, a number of 1024 RNAs and 91 microRNAs were identified to be linked to NEDD4L expression in AML. Among the negatively correlated microRNAs, miR-10a was also discovered as a microRNA that may directly target NEDD4L. Further functional studies revealed that NEDD4L exhibited anti-proliferative and pro-apoptotic effects in leukemic cell line K562. Conclusions Our findings indicated that NEDD4L underexpression, as a frequent event in AML, was associated with genetic abnormalities and prognosis in AML. Moreover, NEDD4L expression may be involved in leukemogenesis with potential therapeutic target value.

NEDD4L mediates ITGB4 ubiquitination and degradation to suppress esophageal carcinoma progression

“…CREB/CRTC2 [26] and miR-1 [27] can regulate NEDD4L expression through transcriptional regulation, while AUF1 [28] and 14-3-3 protein [29] regulate its expression via post-transcriptional regulation, thereby affecting biological functions. NEDD4L variation is discovered in nervous system tumors (like glioma) [30], respiratory system tumors (like lung cancer) [31], digestive system tumors (including gastric cancer, liver cancer, pancreatic cancer and intestinal cancer) [32][33][34], endocrine target organ tumors (breast cancer, ovarian cancer, cervical cancer and prostatic cancer) [35][36][37][38], and hematologic system tumors (leukemia and multiple myeloma) [39,40], which has affected the progression of these tumors. We collected 117 esophageal carcinoma and para-carcinoma tissue samples from Jiangsu University Affiliated People's Hospital and confirmed through Western blot and immunohistochemistry that, the expression of NEDD4L in ESCC tissue was markedly lower than that in para-carcinoma tissues.…”

NEDD4L in human tumors: regulatory mechanisms and dual effects on anti-tumor and pro-tumor

“…Mutations in the NEDD4L gene also affect the prognosis of patients with NSCLC, and a bioinformatic analysis reported that in patients with NSCLC, the NEDD4L rs11660748 A>G and rs73440898 A>G adjusted overall survival hazard ratios were 1.31 and 1.27, respectively, implying that mutations in these two loci may affect patient prognosis (Yang S. et al, 2020). In AML, low NEDD4L expression is significantly associated with younger age at disease onset, higher leukocyte count, and higher numbers of naïve bone marrow/peripheral cells in patients (Chu et al, 2021). Moreover, multivariate analysis shows that NEDD4L expression is an independent prognostic factor in patients with gastric cancer (Gao et al, 2012;Jiang et al, 2019), squamous lung cancer (Sakashita et al, 2013) and glioma (He et al, 2012).…”

“…NEDD4L mRNA was expressed at low levels in acute myeloid leukemia (AML), and low expression was associated with a normal karyotype and Frontiers in Pharmacology frontiersin.org with FLT3 and NPM1 mutations. Additionally, low expression positively correlated with complex karyotypes and TP53 mutations, suggesting that aberrant NEDD4L expression is associated with multiple genetic events in AML (Chu et al, 2021).…”

“…Another study showed that NEDD4L could be directly inhibited by the miR-106b-25, which mediated breast cancer initiation by activating NOTCH1 signaling (Guarnieri et al, 2018). In AML, miR-10a is thought to be a microRNA that may directly target NEDD4L and is inversely correlated with NEDD4L expression (Chu et al, 2021).…”

“…NEDD4L inhibits the proliferation of oral squamous cells by inducing the ubiquitination and degradation of ENO1 (Zhang et al, 2022). NEDD4L has anti-proliferative effects on the leukemia cell line K562 (Chu et al, 2021). LINC00941 interacts with ANXA2 and inhibits NEDD4L-mediated ANXA2 degradation to promote cell proliferation in pancreatic cancer (Wang et al, 2022).…”